Growth differentiation factor-15 (GDF15) as a novel myocardial hormone in heart failure

生长分化因子 15 (GDF15) 作为一种新型心肌激素治疗心力衰竭

• 批准号: 10557842
• 负责人: Michael A Burke
• 金额: $ 43.42万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10557842
• 关键词: Ablation; Activities of Daily Living; Address; Affect; American; Animal Model; Anorexia; Automobile Driving; Biological; Biological Models; Biological Process; Body Composition; Brain; Brain Stem; Cachexia; Calcium; Cardiac; Cardiac Myocytes; Cardiology; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Caregiver Burden; Caring; Cell Compartmentation; Cell Cycle; Cell Nucleus; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Research; Complication; Congestive Heart Failure; Coupled; Data; Data Set; Development; Dilated Cardiomyopathy; Disease; Disease model; Eating; Echocardiography; Event; Fatty acid glycerol esters; Fibroblasts; Fibrosis; Foundations; Future; GDF15 gene; Gene Expression; Genes; Genetic; Genetic Models; Goals; Heart; Heart Transplantation; Heart failure; Histocytochemistry; Hormones; Human; Individual; Ingestion; Investigation; Knock-out; Knockout Mice; Knowledge; Left; Link; Literature; Macrophage; Malignant Neoplasms; Medical; Metabolism; Methods; Modeling; Molecular; Mus; Muscle; Muscle Cells; Muscular Atrophy; Mutation; Myocardial; Myocardial dysfunction; National Heart, Lung, and Blood Institute; Nerve Growth Factor Receptors; Neuroglia; Organ; Pathway interactions; Patients; Persons; Phenotype; Pilot Projects; Prevalence; Prognostic Marker; Prospective Studies; Quality of life; Recombinants; Research; Role; Sampling; Secondary to; Serum; Severity of illness; Signal Pathway; Stress; Structure; Structure of area postrema; Syndrome; System; Testing; Tissues; Toxin; Transgenic Mice; Transplantation Surgery; Tumor-Derived; United States; Weight; Wild Type Mouse; Work; anorexic; cancer cachexia; cardiac cachexia; chemotherapy; clinically actionable; coronary fibrosis; cytokine; experimental study; fat wasting; heart function; immunoregulation; innovation; insight; interstitial; left ventricular assist device; metabolic phenotype; mortality; mortality risk; mouse model; next generation sequencing; novel; novel diagnostics; novel therapeutic intervention; overexpression; paracrine; phospholamban; predictive marker; premature; prevent; prognostic; receptor; reduced food intake; repository; response; stressor; therapeutic target; transcriptome sequencing; transcriptomics

Dilated cardiomyopathy (DCM) is a highly prevalent condition characterized by progressive cardiac dysfunction and interstitial cardiac fibrosis that leads to congestive heart failure (HF) and premature death. As HF progresses, some individuals will develop cardiac cachexia, which limits quality of life, reduces functional capacity, and confers an increased risk of death. Despite this, the molecular mechanisms that underlie cardiac cachexia are completely unknown. This knowledge gap prevents adequate treatment for a complication that may affect as many as 1,000,000 Americans. Delineating the molecular pathways driving cachexia would likely yield clinically actionable evidence that could impact HF care. The present proposal will address this knowledge gap. Growth differentiation factor 15 (GDF15) is a pleiotropic cytokine that can be produced by most organs secondary to a variety of stressors. GDF15 is an exquisitely sensitive biomarker that predicts new-onset cardiovascular events and death in healthy individuals and is highly prognostic in individuals with a wide range of chronic diseases, including HF. Despite this, the biologic function of GDF15 in the heart and in those with HF remains unknown. Recent evidence from animal models and the cancer literature has revealed that GDF15 acts via a very specific receptor, glial cell-derived neurotrophic factor receptor α-like (GFRAL), that is only expressed in the area postrema and nucleus tractus solitarius of the brainstem. In this context, GDF15 suppresses food intake, thus modulating systemic metabolism and reducing food intake. Under stress conditions (i.e., toxin ingestion, as with chemotherapy), this produces an aversive/anorexic response. But, when left unchecked (as when chronically overexpressed}, GDF15 triggers a catabolic-anabolic imbalance that results in cachexia. Evidence also suggests that GDF15 acts in a GFRAL-independent fashion via as-yet undiscovered mechanisms to elicit other responses including immunomodulation, suppression of fibrosis and altered cell cycling. Review of large transcriptomic datasets in the NCBl's GEO repository, including the Pl's earlier transcriptomic work in a genetic model of DCM, reveals that Gdf15 is substantially upregulated in a wide variety of HF models. This exploratory proposal will use genetic mouse models of GDF15 and GFRAL knock-out to study the role of the GDF15-GFRAL axis in cardiac cachexia and in DCM progression. Through detailed phenotyping, basic molecular methods, RNA sequencing and a small clinical pilot study in advanced HF patients, this proposal will lay the foundation for future research on the role of GDF15 in HF and cardiac cachexia. Our proposal is highly innovative and uses robust, unbiased methods to address important questions of great significance to the NHLBI. Our collaborative group brings synergistic expertise on cardiovascular disease models, body composition analysis, clinical research, and next-generation sequencing that will enhance the execution of this proposal. Ultimately, we expect our results will inform new diagnostic and therapeutic strategies for HF, thus targeting a tremendous unmet need in clinical cardiology.

扩张型心肌病（DCM）是一种高度流行的疾病，其特征在于进行性心脏病， 功能障碍和间质性心脏纤维化，导致充血性心力衰竭（HF）和过早死亡。作为 HF进展，一些个体将发展为心脏恶病质，这限制了生活质量，降低了功能， 能力，并增加死亡风险。尽管如此，心脏病的分子机制 恶病质是完全未知的。这种知识差距阻碍了对并发症的充分治疗， 影响了100万美国人描述驱动恶病质的分子途径可能会产生 可能影响HF护理的临床可操作证据。本提案将填补这一知识空白。 生长分化因子15（GDF 15）是一种多效细胞因子，可由大多数器官产生 其次是各种压力源。GDF 15是一种非常敏感的生物标志物，可预测新发 健康个体中的心血管事件和死亡，并且在具有广泛 慢性疾病，包括HF。尽管如此，GDF 15在心脏和HF患者中的生物学功能 仍然未知。来自动物模型和癌症文献的最新证据表明，GDF 15作用于 通过一种非常特异的受体，胶质细胞源性神经营养因子受体α样（GFRAL）， 在脑干的最后区和孤束核。在这种情况下，GDF 15抑制食物 摄入，从而调节全身代谢和减少食物摄入。在应力条件下（即，毒素 摄入，与化疗一样），这产生了厌恶/厌恶反应。但如果不加检查（如 当长期过度表达时，GDF 15触发导致恶病质的分解代谢-合成代谢失衡。 证据还表明，GDF 15通过尚未发现的机制以GFRAL独立的方式发挥作用 以引发其它反应，包括免疫调节、纤维化抑制和细胞周期改变。 审查NCBI的GEO储存库中的大型转录组数据集，包括PI的早期转录组数据集。 在DCM的遗传模型中的工作揭示了Gdf 15在多种HF模型中显著上调。 这项探索性的提议将使用GDF 15和GFRAL敲除的遗传小鼠模型来研究GDF 15和GFRAL基因的作用。 GDF 15-GFRAL轴在心脏恶病质和DCM进展中的作用。通过详细的表型分析， 分子方法，RNA测序和一个小的临床试点研究，在先进的HF患者，这一建议将 为进一步研究GDF 15在HF和心脏恶病质中的作用奠定基础。我们的建议是高度 创新，并使用强大的，公正的方法来解决具有重大意义的NHLBI的重要问题。 我们的合作小组带来了心血管疾病模型、身体组成 分析，临床研究和下一代测序，这将加强这一建议的执行。 最终，我们希望我们的研究结果将为HF的新诊断和治疗策略提供信息，从而针对 临床心脏病学中巨大的未满足需求。